The invention relates to the field of receptors for peptide hormones such as calcitonin.
Calcitonin is a peptide hormone of 32 amino acids that was initially identified as a hypocalcemic factor secreted by the parafollicular cells of the thyroid gland in response to elevations in serum calcium (Copp et al., 1962, Endocrinology 70:638-649). The hypocalcemic effect of calcitonin is mediated primarily by direct inhibition of osteoclast-mediated bone resorption (Friedman and Raisz, 1965, Science 150:1465-1467; Warshawsky et al., 1980, J. Cell Biol. 85:682-694). Calcitonin also enhances renal calcium excretion (Haas et al., 1971, J. Clin. Invest. 50:2689-2702; Warshawsky et al., Supra). In addition to receptors in bone and kidney, high affinity calcitonin binding sites have been demonstrated in many different tissues including the central nervous system, testes, placenta, lung, and on spermatozoa. Cells derived from lung and breast carcinomas, as well as certain lymphoid and myeloid cell lines also express receptors for this hormone. Although the physiologic role of calcitonin in many of these tissues remains poorly understood, its action clearly extends beyond its effects on calcium homeostasis.
The unique ability of calcitonin to inhibit osteoclast-mediated bone resorption has led to its wide-spread use in the treatment of disorders of bone-remodelling, including osteoporosis, Paget's disease of bone and some forms of hypercalcemia of malignancy. In addition, calcitonin has been used in studies to treat pancreatitis and peptic ulcer disease, and to produce centrally mediated analgesia. It has not been established whether all of the pharmacological effects of calcitonin are mediated directly by high affinity calcitonin receptors in these target tissues, or whether they are related to the cross-reaction of calcitonin with receptors for other hormones such as .alpha. or .beta. calcitonin gene related peptide (CGRP) (Wohlwend et al., 1985, Biochem. Biophys. Res. Comm. 131:537-542), or amylin (Zhu et al., 1991, Biochem. Biophys. Res. Comm. 177:771-776), which share similarity in amino acid sequence with calcitonin. .alpha.CGRP is a product of the calcitonin gene produced by differential RNA splicing. .beta.CGRP is a product of a separate gene but differs from .alpha.CGRP by only a single amino acid. These related ligands most likely interact primarily with their own high affinity receptors to produce hormone-specific effects, but at very high concentrations may also cross react with the receptors for the other peptides.